CN107089952A - The method that 5 Flucytosines are prepared using micro passage reaction - Google Patents
The method that 5 Flucytosines are prepared using micro passage reaction Download PDFInfo
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- CN107089952A CN107089952A CN201710322921.3A CN201710322921A CN107089952A CN 107089952 A CN107089952 A CN 107089952A CN 201710322921 A CN201710322921 A CN 201710322921A CN 107089952 A CN107089952 A CN 107089952A
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- reaction
- cytimidine
- fluorine gas
- micro passage
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
Abstract
A kind of method that use micro passage reaction prepares 5 Flucytosines, the cytimidine and fluorine gas being dissolved in using measuring pump in formic acid by flowmeter control cytimidine and fluorine gas in implantation silicon carbide continuous flow reactor, raw material mole the ratio between be 1：1~1：0.77,5 10 DEG C of temperature is controlled, 10wt% cytimidines formic acid solution is flow 580g/h, the volumetric concentration 10vol% fluorine gas flows being blended in nitrogen are 200g/h, collect yellow reaction mixed liquor, n-butanol is added thereto, product Precipitation, filtering, that is, obtain the Flucytosine of target product 5；This method has the advantages that the reaction time is short, product selectivity is preferable, feed stock conversion is higher.
Description
Technical field
It is more particularly to a kind of that 5- fluorine born of the same parents are prepared using micro passage reaction the present invention relates to the preparation field of 5-flurocytosine
The method of pyrimidine.
Background technology
5-flurocytosine, for treating the fungal infection caused by cryptococcus and candida albicans etc., such as mycotic septicemia, the internal membrane of heart
Scorching, meningitis and lung and urethral infection antifungal.Be mainly used in skin and mucosa candidiasis, candida albicans endocarditis,
Candida arthritis, crypotococcal and chromoblastomycosis.Blood phase should be inspected periodically during medication.Liver and kidney function not whole blood
Liquid patient and pregnant woman use with caution；Serious potential renal insufficiency patient disabling.The product contain as treatment serious systemic white abroad
Pearl bacterium and the choice drug of Cryptococcus infections, for fungoid meningitis, fungoid respiratory tract infection and black fungi disease are controlled
Treat.
At present, the synthetic method about 5-flurocytosine mainly has following several：
1：By methylfluoracetate and Ethyl formate condensation reaction, then with urea reaction, then through thionyl chloride chlorination, then ammonia
Water ammonolysis, last sulphuric acid hydrolysis obtain 5-flurocytosine (CN 103435557A).
2：With the fluoro- epoxide pyrimidines of 4- hydroxyls -2- four of 5- through chlorination, ammonification, hydrolysis and be made, synthetic route total recovery
70%.
The route employs toxic articles POCl3 in the use of raw material, and raw materials used species is more, will to equipment
Ask higher, environmental protection pressure is big, and initiation material price, causes the cost of product higher.
3：Precursor 2- methoxyl group -4- hydroxyl-5-fluorine pyrimidines using 5-fluor-uracil or 5-fluor-uracil is initiation materials, warp
Chlorination, ammonification, hydrolysis obtain 5-flurocytosine (Chinese Journal of Pharmaceuticals 1982-08-29, China Medicine University's journal 1989,
20 (1), 35).
This method is primarily present following shortcoming：First, by raw material of 5-fluor-uracil route cost is high, and yield is low (no
Including refining 56.4%), need pressurization to carry out aminating reaction using 5-fluor-uracil precursor as the route of raw material and use a large amount of nothings
Water methanol is unfavorable for industrialized production as solvent, in addition, final step hydrolysis easily makes the amino on pyrimidine ring be converted into hydroxyl
Base, becomes 5-fluor-uracil again again, causes unstable product quality.The synthetic route total recovery is 70%.
4：Cytimidine reacts with halogenating agent at 0~80 DEG C in organic solvent is made intermediate (I)；In obtaining
Mesosome (I) reacts with amino protecting agent at 0~120 DEG C is made intermediate (II)；Obtained intermediate (II) and fluoro reagent
Fluoro-reaction is carried out in polar non-solute or hydrogen fluoride intermediate (III), intermediate is made at 70~200 DEG C
(III) amino deprotection reaction is directly carried out, then 5-flurocytosine (CN 103819412A) is made after separation, purification
Though above-mentioned two kinds of preparation methods can improve yield, reaction complexity, synthetic route length, course of reaction are still suffered from
Middle use organic solvent, the problem of causing environmental pollution.
5：Under inert gas shielding, cytimidine is added into anhydrous hydrogen fluoride, at a temperature of -5~-20 DEG C, is passed through and contains
Fluorine gas carries out fluorination reaction；After reaction 3~5 hours, by reaction solution distillation and concentration, it is dissolved in water, plus alkali regulation reaction solution
After pH value, isolated 5-flurocytosine (201410548354.X).Reaction equation is as follows：
These existing 5-flurocytosine technologies of preparing all use traditional tank reactor, due to being limited by equipment itself
System, has that reaction system heat and mass is relatively slow, reactant air-teturning mixed phenomenon is serious, causes that feed stock conversion is too low, the reaction time
Long, impurity such as increases at the defect.
So far, there is not yet carrying out preparing 5- with cytimidine, fluorine gas, formic acid in the way of micro passage reaction continuous stream
The phonetic technical study of fluorine born of the same parents.The present invention provides a kind of method that use micro passage reaction prepares hydroxy pivalin aldehyde.
Micro passage reaction (Microreactor/Microchannel reactor) is a kind of duct type continuously flowed
Reactor, a kind of characteristic size manufactured by micro-processing technology is between 10-1000 microns, Control of chemical reaction small
The device of reaction compartment.The miniaturization yardstick that microreactor has determines that the transmission of the microfluid of constant flow wherein is special
Property and macroscopical flow behavior.In microreactor narrow microchannel shorten mass transfer away from discrete time, while increase
Specific surface area also provides bigger place for mass transport process, so as to realize real in the range of the quick mixing of reaction mass, Millisecond
Now radially it is thoroughly mixed.The narrow microchannel of microreactor also increases thermograde simultaneously, and the specific surface area of increase is greatly
Enhance the heat-transfer capability (25000W/ (m of reactor2* K)), it is at least order of magnitude greater compared with traditional heat exchangers.Micro- reaction
Device passage equivalent diameter (10-6m) is also smaller than fluids within pipes boundary layer thickness (10-3m) in industrial production, therefore its fluid
Liquid form is laminar flow, and extremely narrow residence time destribution is several without back-mixing.
The big specific surface area of microreactor and continuous operation mode so as to being precisely controlled to be possible for reaction process.
Relative to traditional intermittent reaction technique, microreactor can accurately adjust reaction process condition, such as essence to reaction temperature
Really control, the accurate control to the reaction time and material are uniformly mixed with precise proportions moment.The system miniaturization of microreactor
The reinforcing of chemical process is realized, reaction efficiency greatly improves, reduced the technological requirement of complex chemical reaction and can realize reaction
The quick screening and optimizing of process conditions, so as to deacclimatize chemical reaction process by adjusting consersion unit so that chemical reaction
Speed can be close to its kinetics limit.
, will by the way that flexile chemical technology can be met with reference to difference in functionality supplementary module due to the advantage of microreactor
Ask, it is the strong exothermal reaction that is particularly suitable for use in, the reaction of reactant or unstable products, very strict quick anti-to reaction ratio requirement
Answer, hazardous chemical is reacted and high-temperature high-voltage reaction.
The content of the invention
To solve, the reaction time that above-mentioned prior art is present is longer, product selectivity is poor, feed stock conversion is relatively low
Problem, it is an object of the invention to provide a kind of method that use micro passage reaction prepares 5-flurocytosine, this method has
The advantage that reaction time is short, product selectivity is preferable, feed stock conversion is higher.
To reach above-mentioned purpose, the technical scheme is that：
A kind of method that use micro passage reaction prepares 5-flurocytosine, the born of the same parents in formic acid are dissolved in using measuring pump
Pyrimidine and fluorine gas by flowmeter control cytimidine and fluorine gas in implantation silicon carbide continuous flow reactor, raw material mole the ratio between be
1：1~1：0.77,5-10 DEG C of temperature is controlled, 10wt% cytimidine formic acid solutions are that flow is 500-580g/h, are blended in nitrogen
In volumetric concentration 10vol% fluorine gas flows be 150-200g/h, collect yellow reaction mixed liquor, n-butanol is added thereto,
Product Precipitation, filtering, that is, obtain target product 5-flurocytosine, HPLC purity assays 99.8%, yield 93%；
Reaction equation is as follows：
Further, reaction time of the reaction solution in micro passage reaction is 60~300s；Gained is anti-after reaction
The conversion ratio of raw material cytimidine in liquid is answered to be more than 99%, the selectivity of product 5-flurocytosine is more than 95%.
Further, the concentration of cytimidine formic acid solution is 10wt%, and the fluorine gas volumetric concentration being blended in nitrogen is 10
Or 20vol%.
Further, in micro passage reaction it is temperature that isothermal reactor is controlled by external heat exchanger.
Further, reaction time of the reaction solution in micro passage reaction is 60~240s.
Further, the micro passage reaction has the once-through type passage of tubular structure, and with T-shaped, ball-type, water
The enhancing mixed type passage of drop-wise or heart-shaped structure, passage hydraulic diameter is 0.5mm~10mm.
Further, the present invention is end to end using the enhancing mixed type channel reactor of 4 heart-shaped structures.
Relative to prior art, beneficial effects of the present invention are：
The present invention use micro passage reaction continuous flow process, reaction time from traditional a few hours foreshorten to tens seconds to
A few minutes, significantly improve reaction efficiency.The present invention uses micro passage reaction continuous flow process, and reaction solution is in high-temperature residence
Between it is extremely short, and back-mixing does not occur, therefore side reaction is few, good product selectivity.Meanwhile, present invention selection 1：1~1：0.77 original
Raw material availability and product yield that the control of material mol ratio and flow velocity is significantly improved, the present invention use micro passage reaction
Continuous flow process, relative mixed effect is more preferable in micro passage reaction with traditional caldron process raw material, and reaction temperature is higher, because
This raw material Cytosines rate is high.Preferable technique effect is reached.Possess good commercial application prospect, be worth pushing away on a large scale
Extensively.
Brief description of the drawings
Fig. 1 is the micro passage reaction connection diagram in the present invention.
Embodiment
Technical solution of the present invention is described in further detail with reference to the accompanying drawings and detailed description：
Embodiment 1
As shown in figure 1, using the G1 SiC Reactor consersion units of Dow Corning companies, using measuring pump by born of the same parents
Pyrimidinecarboxylic acid solution (10wt%) and fluorine gas (being blended in nitrogen, volumetric concentration 10vol%) are while be pumped into micro passage reaction
Blender in, micro passage reaction has an once-through type passage of tubular structure, and the enhancing mixed type with T-type structure is logical
Road, controls cytosine solution (10wt% formic acid solutions) flow 580g/h, and fluorine gas (is blended in nitrogen, volumetric concentration
10vol%) flow is to be reacted at 9 DEG C in 200g/h, control microchannel isothermal reactor, and the reaction solution residence time is
300s.Obtain the product liquid containing 5-flurocytosine product.500ml n-butanols are added thereto, white products are separated out, and are crossed and are filtered dry
Dry product 5-flurocytosine, product detects through liquid chromatogram HPLC, as a result for：5-flurocytosine purity is 99.7%, 5- fluorine
The selectivity of cytimidine is 95.2%.
Embodiment 2：
It is using measuring pump that cytimidine formic acid is molten using the G1 SiC Reactor consersion units of Dow Corning companies
Liquid (10wt%) and fluorine gas (being blended in nitrogen, volumetric concentration 10vol%) while be pumped into the blender of micro passage reaction,
Micro passage reaction has the once-through type passage of tubular structure, and the enhancing mixed type passage with T-type structure, and control born of the same parents are phonetic
Pyridine solution (10wt% formic acid solutions) flow 550g/h, fluorine gas (is blended in nitrogen, volumetric concentration 10vol%) flow and is
Reacted in 180g/h, control microchannel isothermal reactor at 5 DEG C, the reaction solution residence time is 240s.Obtain and contain 5- fluorine
The product liquid of cytimidine product.500ml n-butanols are added thereto, separate out white products, it is phonetic that filtration drying obtains product 5- fluorine born of the same parents
Pyridine, product through liquid chromatogram HPLC detect, as a result for：5-flurocytosine purity is 99.3%, and the selectivity of 5-flurocytosine is
96.5%.
Embodiment 3
It is using measuring pump that cytimidine formic acid is molten using the G1 SiC Reactor consersion units of Dow Corning companies
Liquid (10wt%) and fluorine gas (being blended in nitrogen, volumetric concentration 20vol%) while be pumped into the blender of micro passage reaction,
Micro passage reaction has the once-through type passage of tubular structure, and the enhancing mixed type passage with T-type structure, and control born of the same parents are phonetic
Pyridine solution (10wt% formic acid solutions) flow 580g/h, fluorine gas (is blended in nitrogen, volumetric concentration 10vol%) flow and is
Reacted in 150g/h, control microchannel isothermal reactor at 10 DEG C, the reaction solution residence time is 60s.Obtain and contain 5- fluorine
The product liquid of cytimidine product.500ml n-butanols are added thereto, separate out white products, it is phonetic that filtration drying obtains product 5- fluorine born of the same parents
Pyridine, product through liquid chromatogram HPLC detect, as a result for：5-flurocytosine purity is 99.5%, and the selectivity of 5-flurocytosine is
93.2%.
Embodiment 4
It is using measuring pump that cytimidine formic acid is molten using the G1 SiC Reactor consersion units of Dow Corning companies
Liquid (10wt%) and fluorine gas (being blended in nitrogen, volumetric concentration 20vol%) while be pumped into the blender of micro passage reaction,
Micro passage reaction has the once-through type passage of tubular structure, and the enhancing mixed type passage with T-type structure, and control born of the same parents are phonetic
Pyridine solution (10wt% formic acid solutions) flow 500g/h, fluorine gas (is blended in nitrogen, volumetric concentration 10vol%) flow and is
Reacted in 200g/h, control microchannel isothermal reactor at 8 DEG C, the reaction solution residence time is 150s.Obtain and contain 5- fluorine
The product liquid of cytimidine product.500ml n-butanols are added thereto, separate out white products, it is phonetic that filtration drying obtains product 5- fluorine born of the same parents
Pyridine, product through liquid chromatogram HPLC detect, as a result for：5-flurocytosine purity is 99.1%, and the selectivity of 5-flurocytosine is
94.7%.
To improve product yield and reduction experimental cost, applicant has carried out the experiment of multi-parameter to experimental method, found
Yield raising can not also be completely secured using microchannel method, it is necessary to can be only achieved most with reference to appropriate raw material proportioning and flow velocity
Excellent effect, experimental data is as shown in table 1：
As it can be seen from table 1 flow causes product recoveries difference huge, when the flow velocity of cytimidine in raw material is
0.44mol/h, when the flow velocity of fluorine gas is 0.57mol/h, just reaches the optimal yield of product 5-flurocytosine.
The foregoing is only a specific embodiment of the invention, but protection scope of the present invention is not limited thereto, any
The change or replacement expected without creative work, should all be included within the scope of the present invention.Therefore, it is of the invention
Protection domain should be determined by the scope of protection defined in the claims.
Claims (7)
1. a kind of method that use micro passage reaction prepares 5-flurocytosine, it is characterised in that be dissolved in using measuring pump
Cytimidine and fluorine gas in formic acid control cytimidine and fluorine gas in implantation silicon carbide continuous flow reactor, raw material by flowmeter
Mole the ratio between be 1：1~1：0.77,5-10 DEG C of temperature is controlled, 10wt% cytimidine formic acid solutions are that flow is 500-580g/h,
The volumetric concentration 10vol% fluorine gas flows being blended in nitrogen are 150-200g/h, collect yellow reaction mixed liquor, are added thereto
Enter n-butanol, product Precipitation, filtering obtains target product 5-flurocytosine；
Reaction equation is as follows：
2. according to the method described in claim 1, it is characterised in that reaction time of the reaction solution in micro passage reaction
For 60~300s；The conversion ratio of raw material cytimidine is more than 99%, the selection of product 5-flurocytosine in gained reaction solution after reaction
Property be more than 95%.
3. according to the method described in claim 1, it is characterised in that the concentration of cytimidine formic acid solution is 10wt%, is blended in
Fluorine gas volumetric concentration in nitrogen is 10 or 20vol%.
4. according to the method described in claim 1, it is characterised in that controlled by external heat exchanger in micro passage reaction
The temperature of isothermal reactor.
5. according to the method described in claim 1, it is characterised in that reaction time of the reaction solution in micro passage reaction
For 60~240s.
6. according to the method described in claim 1, it is characterised in that the micro passage reaction has the once-through type of tubular structure
Passage, and the enhancing mixed type passage with T-shaped, ball-type, drops or heart-shaped structure, passage hydraulic diameter be 0.5mm~
10mm。
7. method according to claim 6, it is characterised in that the present invention is led to using the enhancing mixed type of 4 heart-shaped structures
Road reactor is end to end.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710322921.3A CN107089952B (en) | 2017-05-09 | 2017-05-09 | Method for preparing 5-fluorocytosine by adopting microchannel reactor |
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| CN201710322921.3A CN107089952B (en) | 2017-05-09 | 2017-05-09 | Method for preparing 5-fluorocytosine by adopting microchannel reactor |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107670603A (en) * | 2017-09-28 | 2018-02-09 | 福建永晶科技有限公司 | A kind of preparation method of micro passage reaction, device and 5 Flucytosines |
| CN110615767A (en) * | 2019-10-26 | 2019-12-27 | 新乡拓新药业股份有限公司 | Method for synthesizing 5-fluorocytosine |
| CN110746360A (en) * | 2019-10-26 | 2020-02-04 | 新乡拓新药业股份有限公司 | Method for synthesizing 5-fluorocytosine |
| CN113185466A (en) * | 2021-04-27 | 2021-07-30 | 宿迁市万和泰化工有限公司 | Novel low-carbon-emission flucytosine production process |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016030662A1 (en) * | 2014-08-29 | 2016-03-03 | University Of Durham | Process for producing fluorocytosine and fluorocytosine derivatives |
| CN106432099A (en) * | 2015-08-10 | 2017-02-22 | 浙江省化工研究院有限公司 | Method for fluorinating pyrimidine derivative by using micro-channel reactor |
-
2017
- 2017-05-09 CN CN201710322921.3A patent/CN107089952B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016030662A1 (en) * | 2014-08-29 | 2016-03-03 | University Of Durham | Process for producing fluorocytosine and fluorocytosine derivatives |
| CN106432099A (en) * | 2015-08-10 | 2017-02-22 | 浙江省化工研究院有限公司 | Method for fluorinating pyrimidine derivative by using micro-channel reactor |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107670603A (en) * | 2017-09-28 | 2018-02-09 | 福建永晶科技有限公司 | A kind of preparation method of micro passage reaction, device and 5 Flucytosines |
| CN107670603B (en) * | 2017-09-28 | 2020-01-17 | 福建永晶科技股份有限公司 | Microchannel reactor, microchannel reactor device and preparation method of 5-fluorocytosine |
| CN110615767A (en) * | 2019-10-26 | 2019-12-27 | 新乡拓新药业股份有限公司 | Method for synthesizing 5-fluorocytosine |
| CN110746360A (en) * | 2019-10-26 | 2020-02-04 | 新乡拓新药业股份有限公司 | Method for synthesizing 5-fluorocytosine |
| CN110615767B (en) * | 2019-10-26 | 2022-06-28 | 新乡拓新药业股份有限公司 | Method for synthesizing 5-fluorocytosine |
| CN110746360B (en) * | 2019-10-26 | 2022-06-28 | 新乡拓新药业股份有限公司 | Method for synthesizing 5-fluorocytosine |
| CN113185466A (en) * | 2021-04-27 | 2021-07-30 | 宿迁市万和泰化工有限公司 | Novel low-carbon-emission flucytosine production process |
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